There has been much debate about whether certain classes of medications (eg, antidepressants) increase the risk of suicidal behavior and whether that risk is greater in children, adolescents, and young adults. In 2004, the FDA placed a black box warning on all antidepressants because of concerns that the medications increase risk of suicidal thoughts and behavior in youths; in 2006, the warning was extended to include young adults (up to age 26). The FDA based its black box warning on results of its meta-analyses of randomized controlled trials (RCTs) conducted in pediatric and adult psychiatric and nonpsychiatric populations.
Questions regarding a possible relationship between antidepressants and suicide were first raised in 1990 with the publication of a series of case reports in which the then newly introduced SSRIs were associated with the apparent emergence of suicidal thoughts and behavior.1 This led to FDA hearings in 1991, but no evidence of an increased risk of suicidal acts associated with antidepressants was found. In October 2004, concerns raised over paroxetine use in children and adolescents eventually led the FDA to issue a black box warning regarding antidepressants and suicide for children younger than 18 years.
The evidence supporting the first black box warning came from a meta-analysis that combined spontaneous reports of suicidal thoughts and behaviors from pediatric RCTs of newer antidepressants, mostly SSRIs.2 The risk of suicidal ideation and behavior, or suicidality, was found to be higher for children treated with antidepressants than for those given placebo (odds ratio [OR] = 1.78; 95% confidence interval [CI], 1.14, 2.77). The FDA also presented results of an analysis of prospective data (suicidal ideation or behavior rating-scale item) that showed no effect for emergence (OR: 0.93; 95% CI: 0.75, 1.15) or emergence and/or worsening of suicidal thoughts and behavior in the active-drug group compared with the placebo group (OR = 0.92; 95% CI, 0.76, 1.11).
The inconsistency between the prospective clinician ratings and spontaneous patient reports has not been adequately explained. It may be due to bias because patients randomized to active drug treatment have a greater likelihood of adverse effects in general, leading to more contact or conversation with study staff and increased chance of having any suicidal thoughts observed. Similarly, overdose on study medication is more likely to be reported if it results in the need for medical attention, as would be true for patients who receive active treatment rather than placebo.
Systematic questioning in a setting such as the emergency department or inpatient service generally gives a more accurate rate of suicidal ideation and behavior than do spontaneous reports. The FDA based its decision on the “signal” of risk from spontaneous adverse-event reports and not on the absence of a signal of risk from systematic clinician evaluations.
In January 2006, the FDA conducted a second meta-analysis of 372 RCTs of newer antidepressants in an adult population of approximately 100,000 patients.3 This analysis was based on spontaneous adverse-event reports from the RCTs and did not provide data from prospective clinician ratings. Overall, the analysis revealed no evidence of more suicide-related adverse reports in the antidepressant group than in the placebo group. Stratification by age showed that for the primary endpoint of suicidal ideation or behavior, for 18- to 24-year-olds, the risk was increased with medication compared with placebo, and the risk approached significance (OR = 1.62; 95% CI, 0.97, 2.71); for adults aged 25 to 64 years, the risk was significantly decreased (OR = 0.79; 95% CI, 0.64, 0.98); and for geriatric patients, the risk was markedly decreased (OR = 0.37; 95% CI, 0.18, 0.76) with antidepressants relative to placebo. On the basis of these results, the FDA extended the black box warning to cover 18- to 24-year-olds.
More recent data
Since the FDA warnings, studies have been conducted to explore the relationship between initiation of antidepressant treatment and suicidal events. We review several lines of evidence that range from the weakest data based on spontaneous reports to the most rigorous data based on RCTs.
Spontaneous reports. Spontaneous reports to the FDA can be made by anyone; most are from patients, physicians, pharmaceutical companies, and plaintiff attorneys. They report both an adverse event and a listing of one or more medications that a patient is taking at the time of the event. Use of the spontaneous reporting systems for drug safety determination is highly problematic. Some limitations regarding these data are:
• Confounding by indication (ie, patients taking a particular drug may have a disease that is itself associated with a higher incidence of the adverse event)
• Systematic underreporting
• Effects of publicity in the media on numbers of reports
• Duplication of reports
• Attribution of the event to a single drug when patients may be taking multiple drugs
• Missing data
These limitations degrade the capacity for optimal data mining and analysis, and any conclusions must be tentative and require validation by another data source.4
Dr Gibbons is Professor of Biostatistics in the departments of medicine, public health sciences, and psychiatry, and Director of the Center for Health Statistics at the University of Chicago. Dr Mann is the Paul Janssen Professor of Translational Neuroscience in the department of psychiatry at Columbia University, and Director, Molecular Imaging and Neuropathology Division, the New York State Psychiatric Institute, New York. The authors report no conflicts of interest concerning the subject matter of this article.
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